OBJECTIVE: The objective of this proposal is to elucidate the pathophysiology of the disease associated with adenosine deaminase deficiency, i.e., severe combined immunodeficiency. APPROACH: Our approach to this problem relies on a potent inhibitor of adenosine deaminase, deoxycoformycin (Ki approximately 10 to the minus 10th power M), to mimic the enzyme deficiency in normal lymphocytes. Our studies are designed to: (a) investigate the levels of adenosine in normal lymphocytes and those treated with the deaminase inhibitor; (b) determine the effects of adenosine on intracellular levels of phosphoribosyl pyrophosphate and cyclic nucleotides in the presence and absence of the inhibitor; (c) assay enzymes related to adenosine in resting lymphocyte and lymphocytes exposed to mitogens in control and drug-treated cells; and (d) quantitate the purine and pyrimidine nucleotide pools in lymphocytes by employing high-pressure liquid chromatography in order to evaluate the effects of adenosine deaminase inhibition on the nucleotide precursor pools required for RNA and DNA synthesis. BIBLIOGRAPHIC REFERENCES: Jackson, R. J. and Keightley, R. G. "A Rapid Radiometric Assay for Adenosine Deaminase," Anal. Biochem., Feb. (1976), in press.